Clinical and experimental studies have pointed to the possible involvement of the transient receptor potential ankyrin type-1 (TRPA1) channels in migraine pain. In this study, we aimed to further investigate the role of these channels in an animal model of migraine using a novel TRPA1 antagonist, ADM_12, as a probe.
Neurotransmitter-gated ion channels adopt different gating modes to fine-tune signaling at central synapses. At glutamatergic synapses, high and low activity of AMPA receptors (AMPARs) is observed when pore-forming subunits coassemble with or without auxiliary subunits, respectively. Whether a common structural pathway accounts for these different gating modes is unclear. Here, we identify two structural motifs that determine the time course of AMPAR channel activation. A network of electrostatic interactions at the apex of the AMPAR ligand-binding domain (LBD) is essential for gating by pore-forming subunits, whereas a conserved motif on the lower, D2 lobe of the LBD prolongs channel activity when auxiliary subunits are present. Accordingly, channel activity is almost entirely abolished by elimination of the electrostatic network but restored via auxiliary protein interactions at the D2 lobe. In summary, we propose that activation of native AMPAR complexes is coordinated by distinct structural pathways, favored by the association/dissociation of auxiliary subunits.
This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (∼10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple ‘molecular switches’ that modulated the mode of pharmacology from activator to inhibitor, as well as engendering varying selectivity profiles for GIRK1/2 and GIRK1/4. Importantly, these compounds were all inactive on nonGIRK1 containing GIRK channels. However, SAR was challenging as subtle structural modifications had large effects on both mode of pharmacology and GIRK1/2 and GIRK1/4 channel selectivity.
A high-performance ultrasonic system for the simultaneous transmission of data and power through solid metal barriers
- IEEE transactions on ultrasonics, ferroelectrics, and frequency control
- Published almost 5 years ago
This paper presents a system capable of simultaneous high-power and high-data-rate transmission through solid metal barriers using ultrasound. By coaxially aligning a pair of piezoelectric transducers on opposite sides of a metal wall and acoustically coupling them to the barrier, an acoustic- electric transmission channel is formed which prevents the need for physical penetration. Independent data and power channels are utilized, but they are only separated by 25.4 mm to reduce the system¿s form factor. Commercial off-the-shelf components and evaluation boards are used to create realtime prototype hardware and the full system is capable of transmitting data at 17.37 Mbps and delivering 50 W of power through a 63.5-mm thick steel wall. A synchronous multi-carrier communication scheme (OFDM) is used to achieve a very high spectral efficiency and to ensure that there is only minor interference between the power and data channels. Also presented is a discussion of potential enhancements that could be made to greatly improve the power and data-rate capabilities of the system. This system could have a tremendous impact on improving safety and preserving structural integrity in many military applications (submarines, surface ships, unmanned undersea vehicles, armored vehicles, planes, etc.) as well as in a wide range of commercial, industrial, and nuclear systems.
The activation mode of the mechanosensitive ion channel, MscL, by lysophosphatidylcholine differs from tension-induced gating
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Published over 3 years ago
One of the best-studied mechanosensitive channels is the mechanosensitive channel of large conductance (MscL). MscL senses tension in the membrane evoked by an osmotic down shock and directly couples it to large conformational changes leading to the opening of the channel. Spectroscopic techniques offer unique possibilities to monitor these conformational changes if it were possible to generate tension in the lipid bilayer, the native environment of MscL, during the measurements. To this end, asymmetric insertion of l-α-lysophosphatidylcholine (LPC) into the lipid bilayer has been effective; however, how LPC activates MscL is not fully understood. Here, the effects of LPC on tension-sensitive mutants of a bacterial MscL and on MscL homologs with different tension sensitivities are reported, leading to the conclusion that the mode of action of LPC is different from that of applied tension. Our results imply that LPC shifts the free energy of gating by interfering with MscL-membrane coupling. Furthermore, we demonstrate that the fine-tuned addition of LPC can be used for controlled activation of MscL in spectroscopic studies.-Mukherjee, N., Jose, M. D., Birkner, J. P., Walko, M., Ingólfsson, H. I., Dimitrova, A., Arnarez, C., Marrink, S. J., Koçer, A. The activation mode of the mechanosensitive ion channel, MscL, by lysophosphatidylcholine differs from tension-induced gating.
CaV1.3 channels regulate excitability in many neurons. As is the case for all voltage-gated channels, it is widely assumed that individual CaV1.3 channels behave independently with respect to voltage-activation, open probability, and facilitation. Here, we report the results of super-resolution imaging, optogenetic, and electrophysiological measurements that refute this long-held view. We found that the short channel isoform (CaV1.3S), but not the long (CaV1.3L), associates in functional clusters of two or more channels that open cooperatively, facilitating Ca(2+) influx. CaV1.3S channels are coupled via a C-terminus-to-C-terminus interaction that requires binding of the incoming Ca(2+) to calmodulin (CaM) and subsequent binding of CaM to the pre-IQ domain of the channels. Physically-coupled channels facilitate Ca(2+) currents as a consequence of their higher open probabilities, leading to increased firing rates in rat hippocampal neurons. We propose that cooperative gating of CaV1.3S channels represents a mechanism for the regulation of Ca(2+) signaling and electrical activity.
- Proceedings of the National Academy of Sciences of the United States of America
- Published 21 days ago
The form and function of river deltas is intricately linked to the evolving structure of their channel networks, which controls how effectively deltas are nourished with sediments and nutrients. Understanding the coevolution of deltaic channels and their flux organization is crucial for guiding maintenance strategies of these highly stressed systems from a range of anthropogenic activities. To date, however, a unified theory explaining how deltas self-organize to distribute water and sediment up to the shoreline remains elusive. Here, we provide evidence for an optimality principle underlying the self-organized partition of fluxes in delta channel networks. By introducing a suitable nonlocal entropy rate ([Formula: see text]) and by analyzing field and simulated deltas, we suggest that delta networks achieve configurations that maximize the diversity of water and sediment flux delivery to the shoreline. We thus suggest that prograding deltas attain dynamically accessible optima of flux distributions on their channel network topologies, thus effectively decoupling evolutionary time scales of geomorphology and hydrology. When interpreted in terms of delta resilience, high nER configurations reflect an increased ability to withstand perturbations. However, the distributive mechanism responsible for both diversifying flux delivery to the shoreline and dampening possible perturbations might lead to catastrophic events when those perturbations exceed certain intensity thresholds.
When conventional high-volume, low-pressure cuffs of endotracheal tubes (ETTs) are inflated, channel formation due to folds in the cuff wall can occur. These channels facilitate microaspiration of subglottic secretions, which is the main pathogenic mechanism leading to intubation-related pneumonia. Ultrathin polyurethane (PU)-cuffed ETTs are developed to minimize channel formation in the cuff wall and therefore the risk of microaspiration and respiratory infections.
- Proceedings of the National Academy of Sciences of the United States of America
- Published about 2 years ago
The past 20 years have witnessed unprecedented progress in brain-computer interfaces (BCIs). However, low communication rates remain key obstacles to BCI-based communication in humans. This study presents an electroencephalogram-based BCI speller that can achieve information transfer rates (ITRs) up to 5.32 bits per second, the highest ITRs reported in BCI spellers using either noninvasive or invasive methods. Based on extremely high consistency of frequency and phase observed between visual flickering signals and the elicited single-trial steady-state visual evoked potentials, this study developed a synchronous modulation and demodulation paradigm to implement the speller. Specifically, this study proposed a new joint frequency-phase modulation method to tag 40 characters with 0.5-s-long flickering signals and developed a user-specific target identification algorithm using individual calibration data. The speller achieved high ITRs in online spelling tasks. This study demonstrates that BCIs can provide a truly naturalistic high-speed communication channel using noninvasively recorded brain activities.
Voltage-gated Na(+) (NaV) channels comprise a macromolecular complex whose components tailor channel function. Key components are the non-covalently bound β1 and β3 subunits that regulate channel gating, expression, and pharmacology. Here, we probe the molecular basis of this regulation by applying voltage clamp fluorometry to measure how the β subunits affect the conformational dynamics of the cardiac NaV channel (NaV1.5) voltage-sensing domains (VSDs). The pore-forming NaV1.5 α subunit contains four domains (DI-DIV), each with a VSD. Our results show that β1 regulates NaV1.5 by modulating the DIV-VSD, whereas β3 alters channel kinetics mainly through DIII-VSD interaction. Introduction of a quenching tryptophan into the extracellular region of the β3 transmembrane segment inverted the DIII-VSD fluorescence. Additionally, a fluorophore tethered to β3 at the same position produced voltage-dependent fluorescence dynamics strongly resembling those of the DIII-VSD. Together, these results provide compelling evidence that β3 binds proximally to the DIII-VSD. Molecular-level differences in β1 and β3 interaction with the α subunit lead to distinct activation and inactivation recovery kinetics, significantly affecting NaV channel regulation of cell excitability.